氯碘羟喹靶向放射增敏抗人肿瘤研究

Radioresistance of tumor has a seriously negative effect on radiotherapy, targeted radiosensitization is a good answer to the problem, there is no ideal targeted radiosensitizer in clinic. We have reported the significant antitumor activity of Clioquinol（CQ） combined with Zinc, recently we have discovered the radiosensitization of CQ+Zinc in human tumor cell lines of Hep-2 and Hela, CQ+Zinc can delay the DNA damage repair of the Hep2 cells irradiated by γ-ray. Other research also reported that zinc can facilitate the DNA damage repair of normal cells. As we know, there is a close relationship between DNA damage repair and radiosensitivity, so we have a hypothesis that CQ+Zinc can targetedly radiosensitize the human tumor cells. To verify the hypothesis, we will treated the different tumor cell lines and nude mice with CQ+Zinc to study the radiosensitization effect and its mechanisms of CQ+Zinc in vitro and in vivo by the the methods of Clonogenic assay and other biomedical techniques, and finally get the optimal dose and pretreatment time of CQ+Zinc；meanwhile, the radioprotection effect of CQ+Zinc on normal cell lines and normal tissue will be investigated in the study. This study will expand the antitumor activity of CQ and provide a new method of tumor targeted radiosensitization.

肿瘤细胞放射抗拒严重影响放疗疗效,肿瘤靶向放射增敏是解决这一问题有效方法，目前临床缺乏理想的靶向放射增敏剂。申请人报道了锌离子载体氯碘羟喹（CQ）联合锌离子具有显著的抗肿瘤活性；还发现CQ联合锌离子可以增加人肿瘤细胞Hep-2和Hela的放射敏感性，抑制Hep-2细胞放射后DNA损伤修复；报道显示锌离子可促进正常细胞DNA损伤修复。DNA损伤修复与放射敏感性密切相关，基于此，本项目提出一个假设：CQ联合锌离子具有肿瘤靶向放射增敏效应。为证实这一假设，我们将通过CQ联合锌离子处理不同组织来源肿瘤细胞和荷瘤裸鼠，应用克隆形成实验和分子生物学等技术，从分子-细胞-动物模型水平，探讨CQ联合锌离子对肿瘤细胞的靶向放射增敏效应、增敏机制、最佳干预方式和对正常细胞和组织放射防护效应。本项目将进一步丰富CQ的抗肿瘤效应，为肿瘤靶向放疗增敏提供新方法。

肿瘤细胞放射抗拒严重影响放疗疗效,肿瘤靶向放射增敏是解决这一问题有效方法，目前临床缺乏理想的靶向放射增敏剂。我们前期报道了锌离子载体氯碘羟喹（CQ）联合锌离子具有显著的抗肿瘤活性。本项目主要探讨了低浓度的CQ联合锌离子对人正常细胞和肿瘤细胞的增殖抑制效应，并研究了低浓度的CQ联合锌离子对多种人肿瘤细胞（Hep-2和Hela）的放射敏感性影响，并深入研究低浓度的CQ联合锌离子影响放射敏感性的机制。克隆形成实验证明低浓度的CQ联合锌离子可以增加人肿瘤细胞Hep-2和Hela的放射敏感性，细胞增殖抑制研究提示相同浓度的CQ联合锌离子人成纤维细胞MRC-5没有毒性。单细胞电泳技术显示低浓度的CQ联合锌离子可以抑制Hep-2细胞放射后DNA单链和双链损伤修复，免疫荧光实验显示CQ联合锌离子可增加2Gy伽马射线辐射后Hela细胞γ-H2AX的表达量。荧光素酶法检测提示低浓度的CQ联合锌离子可以抑制Hela细胞在2Gy伽马射线辐射后NF-κB活性的增高，Westerblot检测提示低浓度的CQ联合锌离子可以下调Hela细胞2Gy伽马射线辐射后ATM蛋白的表达。本项目证明低浓度的CQ联合锌离子可以靶向增加人肿瘤细胞的放射敏感性，并初步探讨其抑制辐射后DNA损伤修复的机制。低浓度的CQ联合锌离子可能是一种新的肿瘤靶向放射增敏剂。

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